PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is an impairing neurodevelopmental disorder and major public health concern, affecting 1% of the population and costing roughly $35 billion annually. Early identification and accurate diagnosis are critical for timely intervention to optimize outcomes. Research initiatives have emphasized familial risk models to delineate early indicators of ASD risk features in infancy and toddlerhood by focusing on infant siblings of children with ASD; however, research recommendations have increasingly recognized the importance of investigating early signs of ASD in populations at high risk for ASD due to a genetic syndrome. Down syndrome is genetic disorder that affects 1 in 700 live births. DS has long been associated with intellectual disability and, more recently, it is clear that children with DS are at significantly elevated risk for ASD as well. Prevalence estimates of ASD in DS range from 5-39%, with a general consensus that at least 20% of individuals with DS meet criteria for ASD. Despite being a leading genetic cause of ASD, DS has been remarkably overlooked in efforts to delineate early ASD risk features, with no published studies on early indicators. As such, this proposal focuses on characterizing early indicators of ASD risk in DS compared to other high- risk groups using a bio-behavioral developmental approach. Specific areas of impairment, including motor, attention, and atypical physiological arousal have been linked to ASD in other high-risk groups; however, it remains unclear whether these features signal risk for ASD in DS as well. This proposal will examine the longitudinal association between these features and ASD risk in DS with comparisons to syndromic ? FXS ? and non-syndromic (siblings of children with ASD; ASIBs) groups at high-risk for ASD. Specifically, the study aims are to 1) characterize bio-behavioral indicators of the ASD risk profile in infants with DS compared to other high-risk groups ? FXS and ASIBs; and 2) determine the longitudinal association of ASD risk indicators during infancy (12 and 24 months) to ASD severity outcomes at preschool (36 months) in DS compared to FXS and ASIBs. Utilizing a developmental, cross-syndrome approach, this proposal aims to clarify the ASD-risk profile in DS, its bio-behavioral indicators during early development, and the extent of phenotypic overlap with other high-risk groups. This proposal leverages a wealth of extant data from ongoing and completed studies with infants and preschool-aged children with FXS and ASIBs that are available to the F32 candidate. This research will be implemented within the outstanding training environment at the University of South Carolina with full research support and under the mentorship of an interdisciplinary team with a very strong record of productivity and successful collaboration. The proposed training plan focuses on 1) gaining mastery in advanced bio-behavioral measurement techniques, including heart activity, eye-tracking, and ASD assessment; 2) developing a strong skillset in advanced longitudinal statistical approaches to study developmental processes; and 3) refining essential professional development skills, including research dissemination, research ethics, grantsmanship, and career transitions. The proposed research and related training experiences will provide the fellow the necessary skillset to develop a programmatic line of research focused on characterizing profiles and indicators of risk outcomes in DS and other populations at risk for ASD.